Genetic regulation of AIF1 shapes immune and liver injury profiles in chronic alcohol use
Priscila C. Antonello, Colin A. Hodgkinson, Dechun Feng, Cheryl Marietta, Baskar Mohana Krishnan, Maria A. Parra, Zhaoli Sun, Bin Gao, David Goldman, Michelle W. Antoine
Priscila C. Antonello, Colin A. Hodgkinson, Dechun Feng, Cheryl Marietta, Baskar Mohana Krishnan, Maria A. Parra, Zhaoli Sun, Bin Gao, David Goldman, Michelle W. Antoine
View: Text | PDF
Clinical Research and Public Health Genetics Hepatology Public Health

Genetic regulation of AIF1 shapes immune and liver injury profiles in chronic alcohol use

Abstract

BACKGROUND In chronic alcohol consumers, immune cells may drive the progression from mild liver injury to more severe alcohol-associated liver disease (ALD), including alcohol-associated hepatitis (AAH) and cancer. Liver macrophages, both resident and infiltrating, express allograft inflammatory factor 1 (AIF1), which is upregulated during inflammation and enhances immune activation.METHODS Using serum and urine samples from 868 individuals classified as having alcohol use disorder or not, based on DSM-IV/V criteria, along with serum and liver biopsy tissue from a second cohort of 27 patients diagnosed with AAH, we evaluated the impact of the AIF1 promoter single-nucleotide polymorphism (SNP) (rs3132451; C/C, C/G, G/G) on liver function markers and immune cell profiles.RESULTS AIF1 transcript levels were genotype dependent: C/C homozygotes expressed 5.2% of the levels observed in G/G individuals, while C/G heterozygotes expressed 46%. Unlike most SNPs associated with harmful effects, the G/G genotype is highly prevalent, present in about 70% of patients. Among chronic alcohol users, G/G individuals exhibited elevated markers of liver injury and a more than 3-fold increase in hepatic immune cells, including infiltrating AIF1+ macrophages and neutrophils. Despite similar durations of alcohol misuse, G/G individuals had higher Model for End-Stage Liver Disease scores compared with C/G individuals, indicating a significantly greater 90-day mortality risk. Notably, some immune abnormalities, such as elevated neutrophils, persisted in G/G males even after alcohol abstinence.CONCLUSION These findings suggest that functional genetic variation in AIF1 may contribute to the severity and persistence of ALD.TRIAL REGISTRATION ClinicalTrials.gov NCT02231840.FUNDING Research support was provided from the National Institute on Alcohol Abuse and Alcoholism of the NIH under grants 1ZIAAA000440-02 and R24AA025017.

Authors

Priscila C. Antonello, Colin A. Hodgkinson, Dechun Feng, Cheryl Marietta, Baskar Mohana Krishnan, Maria A. Parra, Zhaoli Sun, Bin Gao, David Goldman, Michelle W. Antoine

×

Figure 1

The rs3132451 G/G genotype is associated with markedly higher AIF1 expression.

Options: View larger image (or click on image) Download as PowerPoint
The rs3132451 G/G genotype is associated with markedly higher AIF1 expre...
(A) Schematic of the AIF1 gene locus on human chromosome 6p21.33 with flanking genes. Inset shows the location of the rs3132451 SNP (alleles G or C) in the promoter region of the AIF1 gene. (B) Scatter dot plot showing cycle threshold (Ct) values obtained by quantitative reverse transcription PCR for AIF1 and ACTB RNA in cDNA from lymphoblastoid cell lines of individuals with rs3132451 C/G and G/G genotypes. Statistical analysis using a mixed-effects model with Fisher’s LSD post hoc test revealed a significant main effect of SNP genotype (P < 0.0001). Comparison of Ct values between ACTB and AIF1 showed a significant difference (P < 0.0001). ΔCt values are relative to ACTB. A 2-tailed t test comparing AIF1 expression between C/G and G/G genotypes yielded a significant difference (P = 0.027). Each point represents an individual sample; data are shown as the mean ± SEM. *P < 0.05, ****P < 0.0001. (C) The distribution of C/C, C/G, and G/G genotypes among individuals without a diagnosis of alcohol use disorder (non-AUD), with current AUD (CAUD; per DSM-IV/V criteria), and with a lifetime history of AUD but not meeting criteria within the past year (LAUD). Percentages were compared using Fisher’s exact test (α = 0.05). (D) Genotype prevalence by sex across non-AUD, CAUD, and LAUD groups. Statistical analysis was performed using a 2-tailed binomial test (α = 0.05). (E) Same as D, stratified by race. All P values > 0.05. (F) Same as D, stratified by ethnicity. Statistical analysis was performed using a 2-tailed binomial test (α = 0.05). P = 0.0478 for comparisons of C/G and G/G genotype frequencies between non-AUD and CAUD participants who self-identified as Hispanic/Latino.